It is estimated that in the USA approximately one in eight women will develop breast cancer in their lifetime. In 2013 it was predicted that over 230.000 women would be diagnosed with invasive breast cancer and almost 40.000 would die from the disease (ACS Breast Cancer Facts & FIGS. 2013-14). There is therefore a compelling reason to predict which women will develop disease, and to apply measures to prevent it.
A wide body of research has focused on phenotypic risk factors including age, family history, reproductive history, and benign breast disease. Various combinations of these risk factors have been compiled into the two most commonly used risk prediction algorithms; the Gail Model (appropriate for the general population) (also known as the Breast Cancer Risk Assessment Tool: BCRAT) and the Tyrer-Cuzick Model (appropriate for women with a stronger family history).
Breast cancer, like other common cancers, shows familial clustering. Numerous epidemiological studies have demonstrated that, the disease is approximately twice as common in first degree relatives of breast cancer patients. Family studies, and particularly twin studies, suggest that most if not all of this clustering has a genetic basis.
Several breast cancer susceptibility genes have already been identified, most importantly BRCA1 and BRCA2. Mutations in these genes confer a high risk of breast cancer (of the order of 65% and 45%, respectively, by age 70). Mutation screening of population-based series of breast cancer cases has shown that only about 15% of the familial risk of breast cancer can be explained by mutations in these genes. The other known breast cancer susceptibility genes (TP53, PTEN, ATM, CHEK2) make only small contributions to the familial risk (because the predisposing mutations are rare and/or confer only small risks). In total therefore, the known breast cancer susceptibility genes have been estimated to account for no more than 20% of the familial risk.
Genetic variation in risk may result from rare highly-penetrant mutations (such as those in BRCA1 and BRCA2) or from variants conferring more moderate risks. Several lines of evidence suggest strongly that high penetrance mutations are not major contributors to the residual familial risk of breast cancer. Firstly, mutation screening of multiple case families has found that the large majority of cases with a very strong family history (for example four or more affected relatives) harbor mutations in BRCA1 or BRCA2. Secondly, despite extensive efforts over the past nine years, genetic linkage studies have not identified any further linked loci. Thirdly, segregation analyses of large series of breast cancer families have found, after adjusting for BRCA1 and BRCA2, no evidence for a further major dominant breast cancer susceptibility allele.
Germline genetic testing for mutations in BRCA1 and BRCA2 is now routine in genetic medicine and allows for the identification of individuals at significantly increased risk for breast and other cancers. However, such mutations are relatively rare in the general population and account for approximately 10% of all breast cancer cases in the US (approximately half of which are due to BRCA1/2 mutations). The remaining 80% of sporadic breast cancers and those familial cancers for which no causative mutation is known have to be defined by other genetic/clinical markers common to the population at large.
The first commercially available test for assessing the risk of developing breast cancer which relies on the detection of low penetrance polymorphisms was the BREVAGen test described in WO 2010/139006. This test relies on the detection of 7 or 10 single nucleotide polymorphisms. However, there is the need for improved breast cancer risk assessment tests, particularly for non-Caucasian females.